Autoimmune diseases such as multiple sclerosis (MS) may result from the failure of tolerance mechanisms to prevent expansion of pathogenic T cells directed at myelin determinants or other self-tissue antigens. These tolerance mechanisms include CD4+CD25+ regulatory T cells (Treg cells) (Sakaguchi et al., J. Immunol. 155:1151-64, 1995) that may have specificity for TCR determinants (Buenafe et al., J. Neurosci. Res. 76:129-40, 2004; Kumar, J. Clin. Invest. 114:1222-26, 2004). CD4+CD25+ Treg cells represent a unique lineage that maintains central tolerance in the thymus (Sakaguchi, Cell 101:455-58, 2000; Shevach, Ann. Rev. Immunol. 18:423-49, 2000). The Treg cells also exert their regulatory function in the periphery where they constitute ˜5-10% of circulating CD4+ cells. However, peripheral Treg cells may also be induced from CD4+CD25-precursors (Walker et al., J. Clin. Invest. 112:1437-43, 2003).
Treg cells provide a critical level of protection against autoimmunity, transplant rejection and lymphoproliferative disease in several mouse models (Coffer and Burgering, Nature Rev. 4:889-99, 2004). The FOXP3 transcription factor is predominantly expressed by the Treg cell lineage and appears to act as a master regulator for cytokine production and cell-cell contact dependent inhibition of T effector cell activation (Fontenot et al., Nature Immunol. 4:330-36, 2003; Hori et al., Science 299:1057-61, 2003; Khattri et al., Nature Immunol. 4:337-42, 2003; Ramsdell, Immunity 19:165-68, 2003) that may involve membrane-bound perforin molecules (Grossman et al., Immunity 21:589-601, 2004). Recessive X-linked mutations in the FoxP3 gene in scurfy mice (Brunkow et al., Nature Genet. 27:68-73, 2001) and in humans with IPEX (inununodysregulation, polyendocrinopathy and enteropathy, X-linked) (Bennett et al., Nature Genet. 27:20-21, 2001; Gambineri et al., Current Opin. Rheumatol. 15:430-35, 2003; Wildin et al., Nature Genet. 27:18-20, 2001) lead to a fatal lymphoproliferative autoimmune condition.
Multiple sclerosis is a chronic, neurological, autoimmune, demyelinating disease. Multiple sclerosis can cause blurred vision, unilateral vision loss (optic neuritis), loss of balance, poor coordination, slurred speech, tremors, numbness, extreme fatigue, changes in intellectual function (such as memory and concentration), muscular weakness, paresthesias, and blindness. Many subjects develop chronic progressive disabilities, but long periods of clinical stability may interrupt periods of deterioration. Neurological deficits may be permanent or evanescent. In the United States there are about 250,000 to 400,000 persons with MS, and every week about 200 new cases are diagnosed. Worldwide, MS may affect 2.5 million individuals. Because it is not contagious, which would require U.S. physicians to report new cases, and because symptoms can be difficult to detect, the incidence of disease is only estimated and the actual number of persons with MS could be much higher.
The pathology of MS is characterized by an abnormal immune response directed against the central nervous system. In particular, T lymphocytes are activated against the myelin sheath of the neurons of the central nervous system causing demyelination. In the demyelination process, myelin is destroyed and replaced by scars of hardened “sclerotic” tissue which is known as plaque. These lesions appear in scattered locations throughout the brain, optic nerve, and spinal cord. Demyelination interferes with conduction of nerve impulses, which produces the symptoms of multiple sclerosis. Most subjects recover clinically from individual bouts of demyelination, producing the classic remitting and exacerbating course of the most common form of the disease known as relapsing-remitting multiple sclerosis.
Multiple sclerosis develops in genetically predisposed individuals and is most likely triggered by environmental agents such as viruses (Martin et al., Ann. Rev. Immunol. 10:153-87, 1992). According to current hypotheses, activated autoreactive CD4+T helper cells (Th1 cells) which preferentially secrete interferon-gamma (IFN-γ) and tumor necrosis factors alpha/beta (TNF-α/β), induce inflammation and demyelination in MS (Martin et al., Ann. Rev. Immunol. 10:153-87, 1992). Available data suggest that the predisposition to mount a Th1-like response to a number of different antigens is an important aspect of MS disease pathogenesis. Proinflanunatory cytokines (such as IFN-γ, TNF-α/β) and chemokines secreted by Th1 cells contribute to many aspects of lesion development including opening of the blood-brain-barrier, recruitment of other inflammatory cells, activation of resident glia (micro- and astroglia) and the effector phase of myelin damage via nitrogen and oxygen radicals secreted by activated macrophages (Wekerle et al., Trends Neuro Sci. 9:271-77, 1986).
There are currently four approved treatments for relapsing-remitting MS, three types of IFN-β (the Interferon-B multiple sclerosis study group, Neurology 43:655-61, 1993; the IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group, Neurology 45:1277-85, 1995; Jacobs et al., Ann. Neurol. 39:285-94, 1996), and copolymer-1 (Johnson KP, Group tCMST, J. Neural. 242:S38, 1995). Treatment failures have been linked to the development of neutralizing anti-IFN-β antibodies, although their role is also not completely understood at present (the IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group, Neurology 47:889-94, 1996). Failure to respond to IFN-β is not a rare event, and therefore it is important to identify new therapeutic protocols.